Myeloma research on the move

Ludwig, Heinz

doi:10.1038/s41408-021-00550-z

Cited by 2 publications

(3 citation statements)

References 16 publications

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“…It should be noted that multiple myeloma frequently develops resistance to inhibition of various pathways [ 7 ], although the causes of the developed resistance are frequently not known. There are instances of mTORC1 inhibition leading to rebound activation of MAPK via PI3K/AKT [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Multiple myeloma (MM) is an incurable cancer of fast-dividing plasma cells present in the bone marrow, and it frequently develops resistance to various approved drugs, with almost all patients experiencing relapse and succumbing to the disease [ 7 ]. In terms of numbers, MM is the second most common blood-borne malignancy, affecting millions globally [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…In terms of numbers, MM is the second most common blood-borne malignancy, affecting millions globally [ 8 ]. Although chemotherapies, proteasome inhibitors, and immunotherapies have meaningfully improved the 5-year survival in MM patients, as noted above, MM uniformly proves fatal; and new therapeutic drug regimens are required to further increase survival from this cancer [ 7 ]. There is evidence that the Warburg effect is operational in MM, as is also seen with the upregulation of glucose uptake and certain glycolysis enzymes [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma

Nazim

Bishayee

Kang

et al. 2022

Cancers

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Studies in targeting metabolism in cancer cells have shown the flexibility of cells in reprogramming their pathways away from a given metabolic block. Such behavior prompts a combination drug approach in targeting cancer metabolism, as a single compound may not address the tumor intractability. Overall, mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated as enabling metabolic escape in the case of a glycolysis block. From a library of compounds, the tyrosine kinase inhibitor ponatinib was screened to provide optimal reduction in metabolic activity in the production of adenosine triphosphate (ATP), pyruvate, and lactate for multiple myeloma cells; however, these cells displayed increasing levels of oxidative phosphorylation (OXPHOS), enabling them to continue generating ATP, although at a slower pace. The combination of ponatinib with the mTORC1 inhibitor, sirolimus, blocked OXPHOS; an effect also manifested in activity reductions for hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) glycolysis enzymes. There were also remarkably higher levels of reactive oxygen species (ROS) produced in mouse xenografts, on par with increased glycolytic block. The combination of ponatinib and sirolimus resulted in synergistic inhibition of tumor xenografts with no overt toxicity in treated mice for kidney and liver function or maintaining weight.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%